HCV is the causative factor of chronic hepatitis C and, according to statistics by WHO, it is assumed that 170 million people are infected therewith. HCV is a virus classified to the genus Flavivirus in the family Flaviviridae, and it is considered that its infection is caused via blood or a blood component, followed by its growth in the liver. In an infected patient, a relatively mild symptom is observed at the initial stage of infection, but it frequently becomes chronic and leads to development of chronic hepatitis after a certain length of asymptomatic period. As the period of infection becomes longer, the condition of the disease becomes worse to cause liver cirrhosis, leading to liver cancer at high frequency. In 95% of liver cancer, hepatitis viruses are involved, and 80% of such cases are considered to be due to infection with HCV.
HCV has a plus-strand RNA of about 9600 bases as the genome, and it is assumed, based on analysis of the gene sequence, there are at least 6 types of genotypes. The genome of about 9600 bases works as mRNA in a host cell, and a continuous polyprotein having a length of about 3000 amino acids is synthesized, which is cleaved by signal peptidases and signal peptidyl peptidases of the host and proteases encoded by the HCV genome. As a result, 10 types of proteins, that is, the core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B are produced. In addition to this translational frame (open reading frame), there exist the untranslated regions (UTRs) in the 5′-end and the 3′-end, which are responsible for the functions of translational regulation and regulation of replication of the genome.
Among these, the core, E1 and E2 are structural proteins constituting the virus. The virus genome is considered to be packaged by the core protein to form a capsid, and surrounded by the E1 and E2 envelope proteins anchored to the lipid bilayer membrane, thereby forming a virus particle (virion). The function of p7 is not clear, but it is reported to be indispensable for growth of the virus. NS2 is a metal protease and necessary for cleavage of itself, but other functions are not known. NS3 to NS5B are considered to form a complex which works as an RNA replication apparatus together with host proteins, thereby replicating the genomic RNA.
For therapy of chronic hepatitis C, interferon is widely used. In recent years, by virtue of improvements in the formulation of interferon and improvements in the administration method such as a combination therapy with interferon and ribavirin, the rate of successful elimination of HCV from the body, leading to complete response is gradually increasing. However, the rate of complete response by administration of interferon is still about five tenth, and there are many cases where serious side effects are caused by administration of interferon and where administration of interferon cannot be applied to an elderly patient, so that development of a therapeutic method and an agent effective for HCV is demanded.
Infection with HCV occurs via blood or a blood component in human, and, in terms of non-human organisms, anthropoids (chimpanzee) are infected with HCV and the infection causes hepatitis, leading to chronic hepatitis in some cases. However, none of small experimental animals which can be easily kept is known to be infected with HCV at a high rate.
On the other hand, it was revealed that inoculation of serum, which was collected from a surgeon who developed acute hepatitis, to a small primate tamarin causes hepatitis therein. By analyzing blood of the monkey suffering from post-transfusion hepatitis with unknown etiology by molecular biological techniques, two types of viruses, GBV-A and GBV-B, were identified (Non-patent Document 1). Among these, GBV-B was revealed to be most closely related to HCV in view of the molecular structure and to infect New World monkeys such as tamarin and marmoset, inducing hepatitis (Non-patent Document 2). Since HCV has a narrow range of host species and there is no suitable animal model for HCV, the animal model of GBV-B and tamarin is considered to be useful as an alternative model for infection and growth of HCV. However, although the structural similarity between GBV-B and HCV has been confirmed, GBV-B has an amino acid homology of as small as about 28% with HCV. Therefore, even if the animal model of GBV-B and tamarin is used as it is as a development and evaluation system for drugs which specifically act on HCV, it is impossible to carry out screening of drugs which specifically act on HCV.
In order to construct an animal model for HCV using GBV-B, attempts are being made to prepare an HCV/GBV-B chimeric virus by, using the genes of GBV-B as the basis, replacing a part of the genes of GBV-B with the corresponding genes of HCV, or inserting a part of the genes of HCV into the genes of GBV-B. Rijnbrand et al. showed that GBV-B in which a part of its 5′-UTR was replaced with the corresponding 5′-UTR of HCV can infect tamarin (Non-patent Document 3). Further, Haqshenas et al. prepared a chimeric virus by inserting the hyper variable region 1 (HVR1) of HCV into HVR1 in the envelope protein E2 of GBV-B, and infection of marmoset by the chimeric virus was confirmed (Non-patent Document 4). However, the genes in these chimeric viruses are mostly genes from GBV-B, and the chimeric viruses do not have the replication function as HCV. Therefore, these chimeric viruses cannot be said to be useful for development of therapeutic agents for HCV.    [Patent Document 1] WO 2008/136470 A1    [Non-patent Document 1] “Journal of Virology” (USA) 1995, vol. 69, pp. 5621-5630.    [Non-patent Document 2] “Virology” (USA) 1999, vol. 262, pp. 470-478.    [Non-patent Document 3] “Hepatology” (USA) 2005, vol. 41, pp. 986-994.    [Non-patent Document 4] Journal of General Virology (UK) 2007, vol. 88, pp. 895-902.